Polyhydroxylated alkaloids, such as 1-deoxynojirimycin, 1-deoxymannojirimycin, and 1,4-dideoxy-1,4-imino-D-arabinitol, are useful for treatment of carbohydrate-dependent metabolic disorders because of their selective inhibition of glycosidases. Truscheit, E., Frommer, W., Junge, B., Muller, L., Schmidt, D. D., Wingender, W. Angew. Chem. 93 (1981) 738; Angew. Chem., Int. Ed. Engl. 20 (1981) 744. Many polyhydroxylated alkaloids are natural products. For example, 1-deoxynojirimycin has been isolated from plants of genus Morus, Yagi, M., Kouno, T., Aoyagi, Y., Murai, H. Nippon Nogei Kagaku Kaishi 50 (1976) 571; Vasella, A., Voeffray, R. Helv. Chim. Acta. 65 (1982) 1134; 1-deoxynojirimycin also has been isolated from strains of Bacillus, Daigo, K., Inamori, Y., Takemoro, T. Chem. Pharm Bull. 34 (1986) 2243; and, 1-deoxymannojirimycin has been isolated from the legume of Lonchocarpus. Fellow, L. E., Bell, E. A. JCS Chem. Comm. (1979) 977.
Because isolation of these compounds from nature very often is time consuming and relatively expensive, several methods have been developed for preparing these valuable compounds. For example, the synthesis of 1-deoxynojirimycin most often starts with natural sugars. Inouye, S., Tsunuoka, T., Ito, T., Niida, T. Tetrahedron 24 (1968) 2125; Paulsen, H., Sangster, I., Heyns, K. Chem. Ber. 100 (1967) 802; Saeki, H., Ohki, E. Chem. Pharm Bull. 16 (1968) 2477; Paulsen, H., Tadt, K. Adv. Carbohydr. Chem. 23 (1968) 115; Kinast, G., Schedel, M. Angew Chem. Int. Ed. Engl. 20 (1981) 805; Bernotas, R. C., Ganem, B. Tetrahedron Lett. 25 (1984) 165; Bernotas, R. C., Ganem, B. Ibid. 26 (1985) 1123; Setoi, H., Takeno, H., Hashimoto, M. Chem. Pharm. Bull. 34 (1986) 2642; Iida, H., Yamazaki, N., Kibayshi, C. J. Org. Chem. 52 (1987) 3337. Usually, 1-deoxymannojirimycin is synthesized using D-glucose or L-tartrate. Seebach, D., Hungerbuhler "Modern Synthetic Methods" (1980), Scheffold, R., Ed., Salle and Sauerlander-Verlag: Frankfurt and Aarau 2 (1980) 91-171. Synthesis of 1-deoxymannojirimycin starts with D-mannose. Fleet, G. W. J., Smith, P. Tetrahedron Lett. 26 1985) 1469; Fleet, G. W. J., Gough, M. J., Shing, T. K. M. Ibid. 25 (1984) 4029. Of the processes used up to this time, the most efficient are considered to be the combined microbial oxidation/intramolecular reductive amination for 1-deoxynojirimycin, Kinast, G., Schedel, M. Angew Chem. Int. Ed. Engl. 20 (1981) 805, and intramolecular aminomercuration for both 1-deoxynojirimycin and 1-deoxymannojirimycin.
Studies have shown that enzymes such as fructose-1,6-diphosphate (FDP) aldolase can be useful in the synthesis of unusual sugars. Studies on FDP aldolase as a catalyst in enzymatic aldol condensation indicate that the enzyme is very specific for dihydroxyacetone phosphate (DHAP) (or dihydroxyacetone in the presence of arsenate) as the aldol donor, but accepts a variety of aldehydes as acceptors. Wong, C-H, Whitesides, G. M. J. Org. Chem. 48 (1983) 3199; Wong, C-H., Mazenod, F. P., Whitesides, G. M. Ibid. 48 (1983) 3493; Durrwachter, J. R., Drueckhammer, D. G., Nozaki, K., Sweers, H. M., Wong, C-H. J. Am. Chem. Soc. 108 (1986) 7812; Bednarski, M. D., Waldmann, H. J., Whitesides, G. M. Tetrahedron Lett. 27 (1986) 5807. The stereochemistry of the newly formed C--C bond is completely controlled by the FDP aldolase and is the same in all cases.